Abstract Millions of American suffer from osteoarthritis, and current medicines including analgesics and anti- inflammatory drugs only alleviate the symptoms but do not completely cure the disease. The golden treatment so far has been to use replacement auto-grafts and allo-grafts. These grafts however struggle with problems of donor site morbidity, immune-rejection, infection and especially, limit of tissue supply. Engineered cartilage grafts, constructed by seeding stem/chondrogenic cells onto biomaterial scaffolds along with growth factors, have emerged as a compelling alternative tissue source. Despite many encouraging results, clinical use of the engineered cartilage grafts is still limited due to the heavy dependence on toxic growth factors to induce chondrogenesis. As electrical signal has a significant effect on promoting tissue growth and is inherent in living organisms, electrical stimulation (ES) presumably offers a natural and biocompatible approach for inducing cartilage regeneration. Piezoelectric materials with an exciting ability to convert mechanical deformation into electricity, appear to be an appealing platform to create self-powered electrical stimulators which can either harvest mechanical joint-force or be externally stimulated by ultrasound to generate useful ES for cartilage growth. In this regard, the PI has recently developed a novel biodegradable piezoelectric polymer, made of Poly-L-lactide (PLLA), a well-known biocompatible material used for bone scaffolds, surgical sutures and drug- delivery devices. Here, we propose for the first time, a novel approach which employs an injectable piezoelectric collagen-based hydrogel, containing adipose stem cells (ADSCs) and piezoelectric nano- fibers of PLLA, to enhance cartilage regeneration under ultrasound stimulus. Through a minimally- invasive arthroscopic procedure, the hybrid hydrogel solution could be injected into a cartilage defect and spontaneously cured under body temperature to form a cartilage graft in situ. Our main hypothesis is that; this piezoelectric hydrogel can be stimulated by ultrasound to generate useful surface charge which will promote chondrogenesis from the seeded ADSC cells. The project will have three specific aims. Aim 1 is to fabricate and assess the piezoelectric hydrogel. Aim 2 is to assess chondrogenesis of the hydrogel under ultrasound stimulation in vitro. Aim 3 is to demonstrate regenerative capability of the proposed piezoelectric hydrogel in vivo, using a rabbit model with critical size cartilage defects. Milestones: the first milestone is to obtain the piezoelectric stem-cell hydrogel with desired properties after the first 12 months (aim 1). The second milestone is to demonstrate the use of ultrasound stimulation for inducing a significant chondrogenesis in vitro and demonstrate regenerative capability of this cartilage hydrogel in vivo after 2 years (aims 2 and 3). We believe the proposed injectable piezoelectric hydrogel could serve as a powerful platform for the treatment and regeneration of different tissues including not only cartilages but also nerves, bones, muscles etc.